Lose a Protein, Gain an Aggressive Cancer

A protein widely known for squelching cancer appears to be part of a second line of defense: It also keeps cancer cells that do arise from spreading, according to new work. The results shed light on what goes wrong that allows cancers to metastasize; it may even hint at possible approaches to stopping cancer from engaging in its deadly endgame.

While many cancers stay put, some shed cells into the blood; those may wind up elsewhere in the body, where they set up camp, producing deadly metastases. Researchers have long known that a number of proteins help prevent the earliest stages of cancer. A malfunction of one of them, called Raf, leads to both cancer and metastasis. The researchers wondered whether one of the proteins that stops Raf from working, called RKIP (Raf kinase inhibitor protein), might halt only the spread of cancer, but not the growth.

Previous work by molecular biologist Evan Keller at the University of Michigan, Ann Arbor, and his colleagues backed up this idea. In studies of prostate cancer cells cultured from mice, they'd found that metastatic cells produced less RKIP than cells that didn't. The next step was to determine whether RKIP had a role in prostate cancer's spread in humans. The team looked for RKIP in cancers removed from men within hours of their death. They found RKIP in normal prostate tissue and reduced amounts of RKIP in cancer within the prostate, but they could not detect any RKIP protein in cancers that had traveled to other parts of the body.

To verify that loss of RKIP could cause cancer to metastasize, researchers took a roundabout route. They overproduced RKIP in cultured cells that had previously shown metastatic capability; if losing RKIP helped promote metastasis, they reasoned, too much of it should cause a loss of metastatic ability. The hunch proved correct: When Keller's group injected these modified cancer cells into mice, the cancer remained in the prostate. Unmodified cells spread to the mice's lungs, they report in 17 June Journal of the National Cancer Institute.

Tumor biologist Danny Welch of the University of Alabama, Birmingham, says that the work exposes some of the biochemistry behind cancer's spread. Additionally, RKIP and other proteins that anchor a cancer to one site might eventually be targets for gene therapy. "Doctors can cure cancer as long as it doesn't spread," he says, adding that any therapeutic remedies are years in the future.